1. Field of the Invention
The present invention generally relates to propellant compositions used for delivering drugs to patients from metered dose inhalers and, more particularly, to propellant compositions which have reduced or no chlorofluorocarbon content such that their use is environmentally sound.
2. Description of the Prior Art
Metered dose inhalers (MDIs) are, at present, the most efficient and best-accepted means for accurately delivering drugs in small doses to the human respiratory tract. Therapeutic agents commonly delivered by the inhalation route include bronchodilators (B2 agonists and anticholinergics), corticosteroids, and anti-allergics. Inhalation may also be a viable route for anti-infective, vaccinating, systemically acting and diagnostic agents, as well as anti-leukotrienes, and anti-proteases.
MDIs comprise a pressure resistant container typically filled with a product such as a drug dissolved in a liquified propellant or micronized particles suspended in a liquified propellant where the container is fitted with a metering valve. Actuation of the metering valve allows a small portion of the spray product to be released whereby the pressure of the liquified propellant carries the dissolved or micronized drug particles out of the container to the patient. The valve actuator is used to direct the aerosol spray into the patient's oropharynx. Surfactants are usually dissolved in the spray product and can serve the dual functions of lubricating the valve and reducing aggregation of micronized particles.
For many years the preferred propellants used in MDIs were a group of chlorofluorocarbons which are commonly called Freons or CFCs, such as CCl.sub.3 F (Freon 11 or CFC-11), CCl.sub.2 F.sub.2 (Freon 12 or CFC-12), and CClF.sub.2 -CClF.sub.2 (Freon 114 or CFC-114). Often times the propellant used in the MDI is a blend of compounds and the combination of Freon 11, Freon 12, and Freon 114 has been in widespread use in the MDI industry for many years. Chlorofluorocarbons have qualities particularly suitable for use in MDIs including vapor pressures, densities, and elastomer swelling properties which provide respectively for optimal respirable fractions, enhanced suspension stability, and repeatable valve metering.
Recently, however, the use of chlorofluorocarbons per se has come under sharp attack because they are known to deplete stratospheric ozone. Hence, chlorofluorocarbons are considered to be extremely hazardous to the environment. Signatory countries to the Montreal Protocol on Substances that Deplete the Ozone Layer, have resolved to reduce the use of chlorofluorocarbons in a step-by-step fashion over the next ten years and ban their use altogether after the year 2000 a.d. No exemption has been made in the Montreal Protocol for the use of chlorofluorocarbons in MDIs. Therefore, identification of any alternative propellant system(s) which can be used in MDIs will provide an immediate benefit to the MDI industry, and the patients they serve.
Suitable propellant systems may be found in a large number of different classes of halogenated and non-halogenated hydrocarbons including: hydrochlorofluorocarbons (HCFCs) which are alkyl molecules with chloro, fluoro, and hydrogen moieties on the carbon backbone; hydrofluorocarbons (HFCs) which are alkyl molecules with fluoro and hydrogen moieties on the carbon backbone; hydrocarbons (HCs) which include alkane and alkene molecules having only hydrogen moieties on the carbon backbone; fluorocarbons (FCs) which are similar to the HCs except that fluorine moieties are on the carbon backbone instead of hydrogens; and several miscellaneous liquified propellants such as dimethyl ether and ethanol. Compressed gases such as carbon dioxide, nitrogen and nitrous oxide may also provide possible solutions. Propellant systems which use HCFCs are believed to only be temporary solutions because the ozone depleting potential of these compounds may still be a problem. The prior art is replete with examples of propellant systems which employ the above-noted types of compounds; however, few propellant systems have been discovered which are suitable alternatives to the use of chlorofluorocarbons in MDIs.
In the European Patent Application 0,372,777 of Riker Laboratories (hereinafter EP application), there are disclosed several self-propelling aerosol formulations which may be used in MDIs and which may be free from chlorofluorocarbons. The formulations discussed in the EP application comprise a medicament, 1,1,1,2-tetrafluoroethane (HFC-134a), a surface active agent, and an adjuvant compound having a higher polarity than 1,1,1,2-tetrafluoroethane. According to the EP application, the presence of an adjuvant compound of higher polarity than HFC-134a is a critical feature of the preparation of a stable, effective aerosol formulation and states that without a higher polarity adjuvant compound, HFC-134a would be an unsuitable propellant system for use in an MDI. The EP application states further that the preferred solubility parameter, which is somewhat dependent on propellant polarity, ranges between 6.5 and 7.8 (cal/cm.sup.3).sup.1/2 and mixtures having a solubility parameter below 6.0 (cal/cm.sup.3).sup.1/2 would be unacceptable. Vapor pressure is reported to preferably range between 40 and 90 psig and density is reported to preferably range between 1.0 and 1.5 g/cm.sup.3. The EP application states that the preferred ratio of HFC-134a:higher polarity adjuvant compound ranges between 85:15 and 95:5.